U.S. FDA Approves Eliquis® (apixaban) To Reduce The Risk Of Blood Clots Following Hip Or Knee Replacement Surgery
(PRINCETON, NJ and NEW YORK, N.Y., March 14) – Bristol-Myers Squibb
Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE) today announced that the U.S.
Food and Drug Administration (FDA) approved a Supplemental New Drug Application (sNDA) for Eliquis (apixaban) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
"Today's FDA approval of Eliquis for DVT prophylaxis in patients who have undergone hip or knee replacement is a significant milestone for this important medicine, which is also approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation," said Brian Daniels, M.D., senior vice president, global development and medical affairs, Bristol-Myers Squibb. "This approval reflects the continued commitment of the alliance to deliver new treatment options for patients and physicians."
"As the number of hip and knee replacement surgeries performed in the U.S. continues to increase, the risk of DVT following these surgeries remains a concern for physicians," said Steven J. Romano, M.D., senior vice president and Medicines Development Group Head, Global Innovative Pharmaceuticals Business, Pfizer Inc. "Eliquis provides patients and physicians with a new treatment option that offers twice daily oral dosing and no routine coagulation testing, and is broadly accessible through hospitals and managed health care formularies."
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The full Prescribing Information for Eliquis includes Boxed Warnings for the increased risk of stroke in patients with nonvalvular atrial fibrillation who discontinue Eliquis without adequate continuous anticoagulation; and for the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients using Eliquis and undergoing spinal epidural anesthesia or spinal puncture.
Please see complete Boxed Warnings and additional Important Safety Information in this press release.
DVT, a blood clot that forms in a large vein, usually in the lower leg, thigh, or pelvis, can lead to PE when a portion or all of a blood clot breaks off and travels to the lungs, blocking one or more blood vessels. PE can lead to sudden death. Based on recent data, each year in the U.S. an estimated 719,000 total knee replacement surgeries and 332,000 hip replacement surgeries are performed. Patients undergoing hip or knee replacement surgery without thromboprophylaxis are at risk for developing DVT and PE prophylaxis of DVT and PE for most patients undergoing orthopedic surgery.
Guidelines recommend the use of anticoagulants for the "DVT, which may lead to PE, is a serious medical condition," Friedman, M.D., FRCSC, Professor of Orthopaedic Surgery, Medical University of South Carolina. "The FDA approval of Eliquis gives U.S. orthopedic surgeons a new option for DVT prophylaxis in both hip and knee replacement surgery."
This sNDA approval for Eliquis is supported by three clinical trials (the ADVANCE clinical trial program). The ADVANCE trials randomized more than 11,000 patients,
with 5,770 receiving Eliquis and 5,755 receiving enoxaparin, to assess the safety and efficacy of Eliquis.
In December 2013, the FDA accepted for review another sNDA for Eliquis for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE.
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ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
IMPORTANT SAFETY INFORMATION
WARNINGS: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA
(A) Discontinuing ELIQUIS places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of ELIQUIS in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered.
(B) When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins, heparinoids, or Factor Xa inhibitors for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events may be increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Monitor patients for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for- 4 -thromboprophylaxis
• Active pathological bleeding
• Severe hypersensitivity reaction to ELIQUIS (apixaban) (e.g., anaphylactic
WARNINGS AND PRECAUTIONS
• Increased Risk of Stroke with Discontinuation of ELIQUIS in Patients with Nonvalvular Atrial Fibrillation: Discontinuing ELIQUIS in the absence of
adequate alternative anticoagulation increases the risk of thrombotic events. An
increased rate of stroke was observed during the transition from ELIQUIS to
warfarin in clinical trials in patients with nonvalvular atrial fibrillation. If
ELIQUIS must be discontinued for a reason other than pathological bleeding,
consider coverage with another anticoagulant.
• Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious,
potentially fatal bleeding. Concomitant use of drugs affecting hemostasis
increases the risk of bleeding including aspirin and other anti-platelet agents,
other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
Patients should be made aware of signs or symptoms of blood loss and instructed
to immediately report to an emergency room. Discontinue ELIQUIS in patients
with active pathological hemorrhage.
• There is no established way to reverse the anticoagulant effect of apixaban, which
can be expected to persist for at least 24 hours after the last dose (i.e., about two
half-lives). A specific antidote for ELIQUIS is not available. Hemodialysis does
not appear to have a substantial impact on apixaban exposure. Protamine sulfate
and vitamin K would not be expected to affect the anticoagulant activity of
apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, - 5 -
aminocaproic acid) in individuals receiving apixaban. There is neither scientific
rationale for reversal nor experience with systemic hemostatics (desmopressin and
aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents
such as prothrombin complex concentrate, activated prothrombin complex
concentrate, or recombinant factor VIIa may be considered but has not been
evaluated in clinical studies. Activated charcoal reduces absorption of apixaban
thereby lowering apixaban plasma concentrations.
• Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been
studied in patients with prosthetic heart valves and is not recommended in these
The most common and most serious adverse reactions reported with ELIQUIS (apixaban) were related to bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER
ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
• Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. For patients
- 6 -receiving 5 mg twice daily, the dose of ELIQUIS should be decreased when it is
coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp
(e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). In patients already
taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with
strong dual inhibitors of CYP3A4 and P-gp.
• Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use of
ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin,
carbamazepine, phenytoin, St. John's wort) because such drugs will decrease
exposure to apixaban and increase the risk of stroke.
• Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet
agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of
bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-
risk post-acute coronary syndrome patients treated with aspirin or the combination
of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding
with apixaban compared to placebo.
PREGNANCY CATEGORY B
There are no adequate and well-controlled studies of ELIQUIS in pregnant women.
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery.
ELIQUIS should be used during pregnancy only if the potential benefit outweighs the
potential risk to the mother and fetus.
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis decreases thrombin generation and blood clot formation.
Eliquis is approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or knee replacement surgery.
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About Deep Vein Thrombosis and Pulmonary Embolism
DVT is a blood clot in a vein, usually in the lower leg, thigh, or pelvis, which partially or totally blocks the flow of blood. PE is a blood clot blocking one or more vessels in the lungs. DVT causes multiple symptoms including pain, swelling, and redness, and more importantly, can progress to PE, which carries the risk of sudden death.
Please see full Prescribing Information, including BOXED WARNINGS and
Medication Guide, available at www.bms.com.
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize Eliquis, an oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter
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Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the approval of these additional indications in the U.S. will lead to increased commercial success or that ELIQUIS will be approved for any other additional indications. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2013, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
PFIZER DISCLOSURE NOTICE:
The information contained in this release is as of March 14, 2014. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about ELIQUIS (apixaban), including
its potential benefits, that involves substantial risks and uncertainties. Such risks and uncertainties include, among other things, (i) uncertainty regarding the commercial success of the indication for Eliquis for the prophylaxis of DVT in patients who have undergone hip or knee replacement surgery; (ii) whether and when ELIQUIS may be approved by the U.S. Food and Drug Administration (FDA) for the treatment of DVT and PE and for the reduction in the risk of recurrent DVT and PE, as well as the FDA's decisions regarding labeling and other matters that could affect the availability or commercial potential of that additional indication for Eliquis; and (iii) competitive developments.
A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2013 and in its reports on Form 10-Q and Form 8-K.
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